Polyketides are a large family of structurally diverse natural products found in bacteria, fungi, and plants. Many polyketides are clinically important drugs such as erythromycin and tetracycline (antibacterial), daunorubicin and epothilone (anticancer), FK-506 and rapamycin (immunosuppresant), and lovastatin (antihypercholesterolemic). Despite their apparent structural diversity, polyketides share a common mechanism of biosynthesis. The carbon backbone of a polyketide results from sequential condensation of acyl coenzyme (CoA) precursors, and this process, in a mechanistic analogy to fatty acid biosynthesis by the fatty acid synthases (FASs), is catalyzed by the polyketide synthases (PKSs). Much of the current research on polyketide biosynthesis is driven by the following two factors: (1) the extraordinary structure, mechanism, and catalytic reactivity of PKSs that provide an unprecedented opportunity to investigate the molecular mechanism of enzyme catalysis, molecular recognition, and protein-protein interaction and (2) the remarkable flexibility and plasticity of PKSs that allow the production of novel compounds that are difficult to access by traditional chemical synthesis.
The success of the biosynthetic approach depends critically on the availability of novel genetic systems and on genes encoding novel enzyme activities. Of the various polyketide pathways currently being examined, the macrotetrolides, of polyketide origin, offer a distinct opportunity to study the biosynthesis of unique molecular scaffolds. Understanding the mechanisms underlying macrotetrolide production will provide access to rational engineering of macrotetrolide analogues for novel drug leads and also facilitate construction of improved macrotetrolide expression strains by altering specific components of the biosynthetic machinery. In addition, and more importantly, elucidation of the molecular mechanisms of macrotetrolide biosynthesis contribute to the general field of combinatorial biosynthesis by expanding the repertoire of novel PKSs available for use in combinatorial biosynthesis schemes. Consequently, identifying novel PKS mechanisms will further expand the size and diversity of chemical libraries accessible by combinatorial biosynthesis.